Keratoconus (KC) is a non-inflammatory thinning and anterior protrusion of the cornea. This bulging results in steepening and distortion of the cornea, altered refractive powers of the eye (both axial and refractive), and an associated reduction in visual acuity. The cause(s) of KC are unknown. Many hypotheses are based on the association of KC with other conditions, but no unitary theory explains any substantive fraction of the cases of KC. Although KC is an uncommon condition, it is the single most common cause for corneal transplantation in North America and thus carries substantial morbidity and expense. Recently we identified two distinct and independent populations (one from Ecuador, another from Lebanon) in which isolated KC seems to segregate in families either as an autosomal dominant trait with less than uniform penetrance (in Ecuador) or as an autosomal recessive trait (in Lebanon). Our goals for this proposal are to map and to clone the putative KC gene(s) in these populations as a first step toward improved understanding of the molecular pathophysiology of the disorder. To achieve these goals, we will: (1) Identify KC families in each population with more than one affected individual, evaluate clinically both patients and extended family members, analyze the pedigrees, obtain blood samples, isolate genomic DNA, and establish lymphoblastoid cell lines; (2) Determine the genetic map position of the gene(s) responsible for KC in the Ecuadorian and Lebanese families by conventional linkage analysis (affected sib-pair or related genome-wide analyses); (3) Exclude positional candidate genes by a combined positional/functional approach; (4) Identify the gene(s) responsible for KC by positional cloning and study the complete DNA sequence; (5) Test and compare any one isolated gene as a candidate for KC in the other population; and (6) Study the expression pattern of the candidate gene in mouse cornea and embryonic, juvenile, and adult ocular tissues by in situ hybridization to establish an expression profile for each gene. The identification of one or more KC gene has important implications to the under-standing of the patho-physiology of the disease and may open new avenues for therapeutic interventions.